The goal of this proposal is to define the major immunologic, virologic, and genetic factors that are determinants of long-term survival in HIV disease. A consortium of experts has been brought together to conduct these studies. Fresh peripheral blood and lymphoid tissue and cryopreserved specimens from Multicenter AIDS Cohort Study donors will be examined. immunological and genetic aims focus on the role of HIV- specific CD8+ T cell responses because they are the leading candidates for a host determinant of long-term survival. Studies on CD8+ T cell functions will be conducted on MACS donors at UCLA in the laboratory of the Principal Investigator. Genetic associations with long-term survival will be examined by Dr. Dean Mann (National Cancer Institute) in collaboration with this consortium. Drs. John Fahey and Otoniel Maritinez-Maza (UCLA) and Dr. Gene Shearer (National Cancer Institute) will receive specimens through this consortium to allow evaluation of the hypothesis that monokine and lymphokine dysregulation contribute to disease progression. Studies on the virologic determinants of long-term survival will be conducted at UCLA by Dr. Andrew Kaplan to investigate the hypotheses that viral load, replication potential, phenotype and genotype are determinants of the outcome of HIV infection. Overall guidance in the virologic studies will be provided by Dr. Irvin Chen in his role as the Director of the NIH-funded UCLA Center for AIDS Research. Dr. Ashley Haase (University of Minnesota Medical School) will contribute information on HIV infection in lymphoid tissues. Dr. Ronald Desrosiers (New England Regional Primate Research Center) will examine viral sequences from long-term survivor MACS subjects for alterations in their viral regulatory genes. Finally, Dr. Steven Wolinsky (Northwestern University Medical Center) will provide an interface between the studies conducted as a part of the NIH-funded Correlates of Immune Protection in AIDS Vaccine Recipients contract and this project. A number of hypotheses are being tested because multiple mechanisms may be involved in long-term survival. Host and viral determinants are likely to interact and are not mutually exclusive. The studies conducted will test a number of the leading hypotheses in order to define determinants of long-term survival.